Microparticles and polymers for the mucosal delivery of vaccines

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Abstract

Because microparticles are taken up across the gastrointestinal tract following oral administration, they may be exploited for the oral delivery of labile compounds. For example, microparticles have been used for the oral delivery of peptide and protein drugs, and have resulted in improvements in bioavailability. In addition, microparticles have also been exploited for the oral delivery of vaccines, inducing potent immune responses and protective immunity. However, the extent of uptake of microparticles across the gut may limit their potential for oral delivery. Therefore, intranasal immunization is an attractive approach for the induction of mucosal immunity. Microparticles have also been used for the delivery of vaccines to the respiratory tract. In addition to the use of small microparticles to target antigens to mucosal lymphoid tissues, polymeric coatings may also be employed simply to protect antigens against degradation during transit in the gut. Hence, oral delivery using polymers is not necessarily dependent on the uptake of the delivery system across the gut. Recent studies have indicated that a number of polymeric delivery systems possess significant potential for the development of mucosally administered vaccines. However, further work is needed in a number of areas, including the stabilization of antigens within the polymeric delivery systems.

Introduction

The oral route of delivery is the most attractive and acceptable, but is also the most challenging and difficult to exploit for proteins, peptides and other high-molecular-mass molecules. Nevertheless, a live attenuated oral polio vaccine has been successfully marketed for many years and has been used to safely immunize millions of children. Moreover, several additional live attenuated oral vaccines are in late stages of development, including vaccines against rotavirus, Vibrio cholerae and Salmonella typhi. However, many important pathogens cannot be successfully attenuated to allow the development of live mucosally administered vaccines. Moreover, many organisms are difficult or impossible to grow in culture and some cannot be easily manipulated using existing techniques in molecular biology. In addition, it is not yet clear if the available live vectors for mucosal delivery (e.g., Salmonella spp. or polio viruses) can be successfully engineered to express antigens from alternative pathogens. Consequently, there is considerable interest in the development of novel delivery systems for oral administration of vaccines, which can be used to package and deliver a range of antigens from important pathogens. Mainly for reasons of safety, it would be desirable if these novel delivery systems were based on non-living carrier systems, rather than modified bacterial or viral vectors.

Mucosal administration of vaccines offers a number of advantages over the traditional approach to vaccine delivery, which normally involves systemic injection using a needle and syringe. Mucosal delivery of vaccines would avoid the pain and discomfort associated with injections, and would also eliminate the possibility of infections caused by inadequately sterilized needles, or needle re-use. Moreover, mucosal vaccines would be less expensive to produce, since they would not need to be manufactured under such stringent conditions as systemic vaccines. In addition, mucosal vaccines would be less expensive to administer, since trained personnel would not necessarily be required for immunization. Mucosal administration of vaccines might also result in improvements in vaccine efficacy, since mucosal delivery would stimulate mucosal immunity at the sites where most pathogens initially infect hosts. In contrast, systemic immunization does not normally result in the induction of mucosal immunity. The induction of mucosal immunity might prove to be particularly advantageous in the elderly, since unlike systemic immunity, mucosal immunity does not appear to be subject to age-associated dysfunction. Mucosal immunization might also be an attractive approach in the very young, since mucosal immunity appears to develop earlier than systemic immunity. In addition to oral delivery, intranasal immunization is also attractive, since the nose is readily accessible and does not present the problems of low pH and abundant luminal enzymes which are inherent for the oral route. Alternative routes of mucosal immunization which are less attractive, but might be successfully exploited in certain circumstances, include pulmonary inhalation, rectal and ocular immunization.

The use of polymeric microparticles offers significant potential for the development of orally administered vaccines. Microparticles can be prepared from a range of different polymers which can be designed to protect entrapped vaccines against degradation in the gut, to delay the gastric transit of the vaccine or to target vaccines for uptake into the mucosal associated lymphoid tissues (MALTs) of the Peyer's patches (PPs). In addition, similar microparticles can be applied intranasally for the delivery of antigens to the MALTs of the upper respiratory tract. For uptake into the MALT of the gut or the respiratory tract, microparticles need to be prepared with the appropriate dimensions (i.e., <10 μm). As an alternative approach to oral delivery, microparticles may also be designed simply to protect the vaccine against degradation in the gut and to release it in the vicinity of the PPs for subsequent uptake. For this approach, the formulations are usually prepared with much larger dimensions than the microparticles designed for uptake into the MALTs (usually >300 μm). The term “microparticles” will be used in this review to describe a range of polymeric particulate delivery systems, although the real dimensions and characteristics of the delivery systems will be reported whenever possible.

Section snippets

The intestinal uptake of microparticles

A number of researchers have repeatedly demonstrated the uptake of microparticles across the gut following oral administration 1, 2. However, the reported sites of uptake and the mechanisms involved have differed. Overall, four alternative sites and mechanisms of uptake have been emphasized; the villus tips, intestinal macrophages, ordinary enterocytes and the epithelium of the Peyer's patches. It is possible that all of these mechanisms may be operating simultaneously to some extent.

The

Microparticles for oral delivery of drugs

On a number of occasions, particulate delivery systems have been used to enhance the bioavailability of drugs which are normally poorly absorbed following oral administration [24]. Table 2 lists some of the microparticles used as drug delivery systems. Maincent et al. [25]enhanced the oral bioavailability of vincamine in rabbits by adsorption to cyanoacrylate nanoparticles (230 nm). In addition, cyanoacrylate nanoparticles (300 nm) have also been used to enhance the oral absorption of insulin

Microparticles for oral delivery of vaccines

The ability of polymeric microparticles to induce enhanced antibody responses to associated antigens following systemic administration has been known for some time [34]. It is also well established that particulate antigens are more effective for oral immunization than soluble antigens 35, 36. The ability of particulate antigens to induce enhanced immune responses following oral immunization is mainly a consequence of their greater uptake into intestinal Peyer's patches [8]. In the early 1980s,

Enteric-coating of vaccines

Several alternative approaches to the oral administration of vaccines using polymeric delivery systems other than PLGs have also been described, and these approaches have previously been reviewed [24]. One approach involves the use of enteric coating polymers, which are designed to protect the vaccine against low pH in the stomach and to release it in the intestine. Klipstein et al. [88]described the encapsulation of the B subunit of heat-labile enterotoxin (LTB) in an enteric coated

Alternative approaches to oral immunization with polymeric delivery systems

Several additional approaches to the oral delivery of vaccines have been described, which involve the encapsulation or entrapment of vaccine antigens in protective polymer coatings. A novel approach to oral immunization in ruminants was described by Bowerstock et al. [65]. Culture supernatants of Pasteurella haemolytica, a pulmonary pathogen in bovines, was absorbed into poly(methacrylic acid) hydrogels and orally administered to calves. Each of the calves were administered 300 hydrogels per

Conclusions

Mucosal delivery of vaccines, particularly involving the oral route, offers a number of significant advantages over systemic delivery. Most notably, mucosal delivery involves easy administration and improved safety. In addition, unlike systemic immunization, mucosal delivery results in the induction of the secretory immune response, through secretory IgA. There are many alternative approaches to the mucosal delivery of vaccines, involving a range of different delivery systems or vectors 102, 103

Acknowledgements

I would like to acknowledge the contributions made by my various collaborators and colleagues to my own publications included in this review.

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